School of Pharmacy
David J. Lapinsky
Fully-Functionalized Small-Molecule Probes, Multicomponent Reaction, Chemical Biology, Phenotypic Screening
A lack of new drug targets and drug mechanisms, coupled with drug-pipeline attrition, represent significant problems in oncology drug discovery. Towards addressing this challenge, “fully-functionalized small-molecule probes” (FFSMPs) have been established, which are compounds that can be immediately used as “bait” to capture their protein targets under the same assay conditions used for oncology-based phenotypic screening. Specifically, each FFSMP library member contains one or more structural-diversity elements to promote interactions of the probe with different protein targets in living cells, an electrophile or photoreactive functional group for covalent attachment of the probe to interacting proteins via affinity or photoaffinity labeling, and a terminal alkyne click chemistry handle for visualization, enrichment, and identification of probe-interacting proteins. In particular, direct phenotypic screening of FFSMPs has been shown to facilitate the discovery of pharmacologically-active probes that are readily amenable to mechanistic characterization and accelerated target identification using advanced chemoproteomic techniques. However, there is an urgent/critical need for FFSMPs with increased structural diversity in order to sample a larger amount of chemical space towards discovering new drug candidates, drug targets, and drug mechanisms in the battle against cancer.
The overall objective of my research is to synthesize structurally-diverse FFSMPs via one-pot isocyanide based multicomponent reactions that are capable of sampling a large amount of chemical space during integrated cancer-based phenotypic screening and target identification studies. My research focuses on a clickable trifunctional monomer toolkit, which allows for high chemical scaffold diversity. The rationale that underlies the research is that studies involving FFSMPs are capable of producing ligands for proteins that have yet to be described and can reveal a diverse array of traditional or non-traditional druggable targets in cells, both of which have the exciting potential to shift research efforts in completely new directions yet to be realized.
Swank, C. (2021). Towards a "Universal Chemical Biology Toolbox" for Tackling Human Diseases (Master's thesis, Duquesne University). Retrieved from https://dsc.duq.edu/etd/2026